Let-7i-5p Mediates the Therapeutic Effects of Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells on Mitigating Endotoxin-Induced Mortality and Liver Injury in High-Fat Diet-Induced Obese Mice

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 1; p. 36
• Main Authors: Chang, Chao-Yuan, Chen, Kung-Yen, Shih, Hung-Jen, Chiang, Milton, Huang, I-Tao, Huang, Yen-Hua, Huang, Chun-Jen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.12.2021; MDPI
• Subjects: Apoptosis; exosomes; Glucose; Granulocytes; Hypoxia; Inflammation; let-7i; Liver; Metabolism; MicroRNAs; Mortality; Obesity; Oxidation; Oxidative stress; Plasma; Sepsis; Stem cells; Tumor necrosis factor-TNF; Weight control; let-7i; liver; exosomes; obesity; sepsis
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15010036

Obesity complicates sepsis and increases the mortality of sepsis. We examined the effects of exosomes (from human placenta choriodecidual membrane-derived mesenchymal stem cells, pcMSCs) on preventing sepsis in obesity and the mitigating role of hsa-let-7i-5p microRNA. Obese mice (adult male C57BL/6J mice fed a high-fat diet for 12 weeks) received normal saline (HFD), endotoxin (10 mg/kg, intraperitoneal (ip); HFDLPS), endotoxin with exosomes (1 × 10 particles/mouse, ip; HLE), or endotoxin with let-7i-5p microRNA inhibitor-pretreated exosomes (1 × 10 particles/mouse, ip; HLEi). Our data demonstrated that the 48-h survival rate in the HLE (100%) group was significantly higher than in the HFDLPS (50%) and HLEi (58.3%) groups (both < 0.05). In the surviving mice, by contrast, levels of liver injury (injury score, plasma aspartate transaminase and alanine transaminase concentrations, tissue water content, and leukocyte infiltration in liver tissues; all < 0.05), inflammation (nuclear factor-κB activation, hypoxia-inducible factor-1α activation, macrophage activation, and concentrations of tumor necrosis factor-α, interleukin-6, and leptin in liver tissues; all < 0.05), and oxidation (malondialdehyde in liver tissues, with < 0.001) in the HLE group were significantly lower than in the HFDLPS group. Levels of mitochondrial injury/dysfunction and apoptosis in liver tissues in the HLE group were also significantly lower than in the HFDLPS group (all < 0.05). Inhibition of let-7i-5p microRNA offset the effects of the exosomes, with most of the aforementioned measurements in the HLEi group being significantly higher than in the HLE group (all < 0.05). In conclusion, exosomes mitigated endotoxin-induced mortality and liver injury in obese mice, and these effects were mediated by let-7i-5p microRNA.